Field of the Invention
The present invention relates to a novel phytospingosine-1-phosphate derivative, a preparation method therefor, and a composition comprising the same for preventing and treating hair loss or for growing hair, and more particularly, to a novel phytospingosine-1-phosphate derivative useful for preventing and treating hair loss or for growing hair, a preparation method therefor, a cosmetic composition comprising the same for preventing hair loss or for growing hair, and a pharmaceutical composition comprising the same for preventing and treating hair loss or for growing hair.
Description of the Related Art
Sphingosine-1-phosphate among sphingo lipids is a physiologically active autocrine molecule that induce a physiological reaction by binding to endothelial differentiation gene, EDG (non-patent literature 1), and are produced by sphingosine kinase and degraded by lyase or sphingosine phosphatase (non-patent literature 2).
The dynamic balance in the amounts of sphingolipid metabolites, e.g., ceramide and sphingosine 1-phosphate, and the control of reverse signal process are important factors in determining the life and death of cells (refer to Non-Patent Document 3). Ceramides have double-sided characters as follows: ceramides existing in an increased amount in cells, e.g., cancer cells, inhibit proliferation of the cancer cells while ceramides existing in an increased amount in cells, e.g., inflammatory cells, worsen inflammatory responses. Recently, new functions of sphingolipids, i.e., involvement of ceramides in apoptosis, cell proliferation inhibition, and neurite formation in the nervous system, and the importance of the structure of sphingomyelin in cellular transportation have been suggested. That is, it is believed that three-dimensional asymmetry in endomembrane and outer membrane of cells and non-uniformity of horizontal structures of sphingolipids are involved in various cellular functions, such as differentiation, proliferation, and secretion. In addition, in regard to new functions of sphingolipids, the presence of a mechanism is suggested in that glucosylceramide is accumulated in cells resistant to anti-cancer agents, the resistant cells converting ceramides, which are apoptosis-inducing factors, into other metabolites, such as glycosphingolipids that are accordingly excluded (refer to Non-Patent Document 4). Therefore, it is believed that changes in the amount of sphingolipids may be likely to be involved in blood tumor or conditions of neurological diseases (refer to Non-Patent Document 5).
In this regard, sphingosine-1-phosphate, which is an important intermediate in the metabolism of sphingosine, exhibits a variety of biological activates, and accordingly, many studies have focused on production, metabolism, action, and synthesis methods of sphingosine-1-phosphate (refer to Non-Patent Document 6). However, studies on phytospingosine-1-phosphate, which serves a comparable role with sphingosine-1-phosphate, are extremely limited, and even if studies on phytospingosine-1-phosphate exist, they mainly focus on in vivo roles of phytospingosine-1-phosphate. Preparation methods of these two substances, i.e., sphingosine-1-phosphate and phytospingosine-1-phosphate, are classified into an enzymatic synthesis method using kinase and a chemical synthesis method. The enzymatic synthesis methods described herein are all limited in terms of identifying a structure of a final product (refer to Non-Patent Documents 7, 8, and 9). Although a relatively large number of studies were made regarding a chemical synthesis method of D-sphingosine-1-phosphate, studies on a chemical synthesis method of D-phytospingosine-1-phosphate e- is found only in three thesis papers (refer to Non-Patent Documents 10, 11, and 14). However, these two synthesis methods are performed in the same manner as in the synthesis method of D-sphingosine-1-phosphate (refer to Non-Patent Documents 12 and 13), except that sphingosine was substituted by phytospingosine to be used as a starting substance.
A synthesis method of D-phytospingosine-1-phosphate according to Reaction Equation 1 below has been disclosed as the first chemical synthesis method (refer to Non-Patent Document 10).

It is reported that the final yield of the entire process of the synthesis method above is about 43%, and there are provided data for high-performance FAB-MS and 1H-NMR in regard to the final product, D-phytospingosine-1-phosphate.
Another synthesis method of D-phytospingosine-1-phosphate according to Reaction Equation 2 below has been also disclosed (refer to Non-Patent Document 14).

The synthesis methods above consist of 6 steps in total, and it is reported that the final yield of the entire process thereof is about 14.2%. There are provided spectroscopic data for all the intermediates, but detailed spectroscopic data for the final target substance, D-phytospingosine-1-phosphate, is not reported.
Therefore, it is believed that the D-phytospingosine-1-phosphate is a significantly inefficient substance in terms of synthesis thereof since its yield is very low as much as 43% or less according to the synthesis methods above.
The phytospingosine-1-phosphate, which is also recognized as a substance having an equivalent or greater hair growth and restoration efficacy with that of minoxidil, is patented for disclosing use of phytospingosine-1-phosphate derivative for preventing and treating hair loss or for growing hair (refer to Patent document 1). There are various causes of alopecia, i.e., a loss of hair from the scalp, and alopecia can be caused largely by action of male hormones, psychological stress, accumulation of lipid peroxide in the scalp, side effects of drugs, chronic diseases, such as leukemia or tuberculosis, side effects of radiation therapy, malnutrition, and the like. In addition, hair loss that has been known as concerns of the male recently becomes an issue for the female and the young who requiring a large demand for prevention and treatment of hair loss.
Drugs that are currently used for promoting hair growth or that are currently used as hair tonics can be largely divided into vasodilators for circulating sufficient blood to the scalp, female hormones for inhibiting the action of male hormones, and androgen inhibitors for inhibiting 5α-reductase that converts testosterone into 5-dihydrotesteone (5-DHT). Examples of the vasodilators include Carpronium Chloride, minoxidil, and various plant extracts, examples of the female hormones include estrogen, estradiol, and progesterone, and examples of the androgen inhibitors include finasteride and pentadecanoic acid.
However, due to the insufficient efficacy or side effects of the above-described therapeutic agents for hair loss, the development of more effective and safe drugs for treating hair loss or growing hair is needed. In the case of minoxidil used for topical or oral administration, the skin irritation such as scalp redness, inflammation, infection, irritation or pain is caused. In addition, due to the antihypertensive effect of minoxidil, there is a problem of requiring careful administration to patients with hypertension including patients being treated with an antihypertensive drug. In the case of finasteride, due to its inhibitory effects on hormonal activity, it has the disadvantages of erectile dysfunction and decreased sexual desire.
The phytospingosine-1-phosphate derivative is effective to promote angiogenesis, and thus is recognized as a substance with purposes of preventing and treating hair loss or for growing hair. In addition, the phytospingosine-1-phosphate derivative can be used without concerning the side effects of the conventional therapeutic agents for hair loss, the side effects including antihypertensive effects or decreased sexual functions.
However, as described above, the phytospingosine-1-phosphate is a substance having a low synthesis yield, and thus, the development of a substance that can be synthesized in high yields and that is effective in hair loss treatment without the side effects caused by conventional therapeutic agents for hair loss is necessary.